EP0526540A1 - Use of 5-ht 4? receptor antagonists in the treatment of arrythmias and stroke - Google Patents

Use of 5-ht 4? receptor antagonists in the treatment of arrythmias and stroke

Info

Publication number
EP0526540A1
EP0526540A1 EP91908623A EP91908623A EP0526540A1 EP 0526540 A1 EP0526540 A1 EP 0526540A1 EP 91908623 A EP91908623 A EP 91908623A EP 91908623 A EP91908623 A EP 91908623A EP 0526540 A1 EP0526540 A1 EP 0526540A1
Authority
EP
European Patent Office
Prior art keywords
stroke
treatment
cardiac
receptor antagonists
arrythmias
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP91908623A
Other languages
German (de)
French (fr)
Other versions
EP0526540B1 (en
Inventor
Alberto Julio Kaumann
Francis David Dr. King
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Smith Kline and French Laboratories Ltd
Original Assignee
Beecham Group PLC
Smith Kline and French Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group PLC, Smith Kline and French Laboratories Ltd filed Critical Beecham Group PLC
Publication of EP0526540A1 publication Critical patent/EP0526540A1/en
Application granted granted Critical
Publication of EP0526540B1 publication Critical patent/EP0526540B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to a novel method of medical treatment, in particular the treatment and prevention of human atrial arrhythmias and the prevention of stroke.
  • 5-HT receptors which may resemble those known to exist in the CNS, have been identified in the human atrium [Br. Journal of Pharmacology, 98, 664p, (1989) and Br. Journal of Pharmacology, 100, 879-885 (1990)]. These M 5-HT 4 -like n receptors located in the atrium are hereinafter referred to as cardiac 5-HT receptors.
  • the present invention therefore provides the use of cardiac 5-HT 4 receptor antagonists in the treatment of human atrial arrhythmias.
  • Cardiac arrhythmias have been associated with symptomatic cerebral embolism. Cerebral embolism is the most common cause of ischaemic stroke and the heart, the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation (Harrison's Principles of Internal Medicine, 11th Edition) . Up to 9% of individuals over the age of 60 have atrial fibrillation (Sirna et al. 1990, Stroke 21; 14-22) .
  • Atrial fibrillation in combination with rheumatic valvular heart disease is associated with a 17-fold increased risk of stroke
  • chronic atrial fibrillation without rheumatic valvular heart disease is associated with a 5-fold increased risk of stroke.
  • arrhythmias which encourage atrial stasis such as atrial fibrillation and atrial disorders cause cerebral and systemic embolism.
  • specific cardiac 5-HT 4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT would also be expected to reduce occurrence of stroke.
  • the present invention therefore provides in a further aspect, the use of cardiac 5-HT receptor antagonists for reducing the occurrence of stroke.
  • the compound (3- ⁇ -tropanyl)- lH-indazole-3-carboxylic acid ester has been found to be a cardiac 5-HT 4 receptor antagonist and is expected to be of use in the treatment of the conditions hereinbefore defined.
  • the cardiac 5-HT 4 receptor antagonists When used in therapy, the cardiac 5-HT 4 receptor antagonists are usually formulated in a standard pharmaceutical composition.
  • the present invention therefore provides pharmaceutical compositions comprising a cardiac 5-HT 4 receptor antagonist in association with a pharmaceutically acceptable carrier.
  • the compositions can be prepared by methods well known in the art of pharmacy, for example, compounds which are active when given orally can be formulated as liquids, for example, syrups, suspensions or emulsions., tablets, capsules and lozenges.
  • Liquid formulations will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) , for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycols, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycols, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • Tablet compositions can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • compositions in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • the composition is in unit dose form such as a tablet or capsule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • (3- ⁇ -Tropanyl)-lH-indazole-3-carboxylic acid ester can be prepared by the procedures described in EP-200444-A.
  • the tissue was set up in an apparatus with a 50 ml. bath (Blinks, 1965 J. Appl. Physiol. 20, 755-757), containing the solution described above supplemented with (mM) :15 Na + , 5 fumarate, 5 pyruvate, 5 L-glutamate, 10 glucose. Experiments were carried out at 37°C.
  • the spontaneously beating right atrium was suspended at a resting tension just sufficient for measurable development of tension (to avoid tachycardia induced by stretching the sinoatrial node - Blinks, 1956 Amer. J. Physiol. 186, 299-303) .
  • the tissue was attached to a Swema SG4-45 strain gauge transducer by means of a stainless steel wire and force recorded on a Watanabe polygraph.
  • a single cumulative concentration-effect curve was determined by the sequential addition of 5-HT or other agonists to the bath in amounts that increased the total concentration in steps of log unit. Enough time was allowed for each effect to reach equilibrium. The experiments were terminated by the administration of a saturating concentration of (-)-isoprenaline (0.2 mM) . The time of incubation with an antagonist was at least 1 hr before a concentration-effect curve for an agonist was determined.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Mechanical Treatment Of Semiconductor (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)
  • Polarising Elements (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)

Abstract

The use of cardiac 5-HT4 receptor antagonists in the treatment of atrial arrythmias and for reducing the occurrence of stroke.

Description

1USE OF 5-H 4 ΕmΕX SSWRt RQOmSIS IN THE TREATMENT OF ARRHYTHMIAS AND STROKE
The present invention relates to a novel method of medical treatment, in particular the treatment and prevention of human atrial arrhythmias and the prevention of stroke.
Compounds which antagonise the effects of 5-HT4 receptors in the central nervous system, and gastro- intestinal system are known in the art (see for example European Journal of Pharmacology, 146 (1988), 187-88, Naunyn-Schmiedeberg's Arch.Pharmacol. (1989) 340:403-410) and Br. Journal of Pharmacology 96:247p. 1989) .
In addition, 5-HT receptors which may resemble those known to exist in the CNS, have been identified in the human atrium [Br. Journal of Pharmacology, 98, 664p, (1989) and Br. Journal of Pharmacology, 100, 879-885 (1990)]. These M5-HT4-liken receptors located in the atrium are hereinafter referred to as cardiac 5-HT receptors.
However, in spite of these disclosures there is no indication as to the potential clinical usefulness of compounds which block cardiac 5-HT receptors.
It has now been found that the compound (3-α-tropanyl)-lH-indazole-3-carboxylic acid ester antagonises cardiac 5-HT4 receptors and is expected, as a consequence, to be of use in the treatment of atrial arrhythmias.
The present invention therefore provides the use of cardiac 5-HT4 receptor antagonists in the treatment of human atrial arrhythmias. Cardiac arrhythmias have been associated with symptomatic cerebral embolism. Cerebral embolism is the most common cause of ischaemic stroke and the heart, the most common source of embolic material. Of particular concern is the frequency of embolism associated with atrial fibrillation (Harrison's Principles of Internal Medicine, 11th Edition) . Up to 9% of individuals over the age of 60 have atrial fibrillation (Sirna et al. 1990, Stroke 21; 14-22) . Atrial fibrillation in combination with rheumatic valvular heart disease is associated with a 17-fold increased risk of stroke, whereas chronic atrial fibrillation without rheumatic valvular heart disease is associated with a 5-fold increased risk of stroke. Only arrhythmias which encourage atrial stasis, such as atrial fibrillation and atrial disorders cause cerebral and systemic embolism. Thus, specific cardiac 5-HT4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT, would also be expected to reduce occurrence of stroke.
The present invention therefore provides in a further aspect, the use of cardiac 5-HT receptor antagonists for reducing the occurrence of stroke.
As indicated above, the compound (3-α-tropanyl)- lH-indazole-3-carboxylic acid ester has been found to be a cardiac 5-HT4 receptor antagonist and is expected to be of use in the treatment of the conditions hereinbefore defined.
When used in therapy, the cardiac 5-HT4 receptor antagonists are usually formulated in a standard pharmaceutical composition. The present invention therefore provides pharmaceutical compositions comprising a cardiac 5-HT4 receptor antagonist in association with a pharmaceutically acceptable carrier. The compositions can be prepared by methods well known in the art of pharmacy, for example, compounds which are active when given orally can be formulated as liquids, for example, syrups, suspensions or emulsions., tablets, capsules and lozenges.
Liquid formulations will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) , for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycols, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
Tablet compositions can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
Compositions in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Preferably, the composition is in unit dose form such as a tablet or capsule.
Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
DATA
(3-α-Tropanyl)-lH-indazole-3-carboxylic acid ester can be prepared by the procedures described in EP-200444-A.
PIGLET SPONTANEOUS BEATING ATRIA SCREEN
Method (See A. J. Kaumann, 1990, Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622).
Piglets of either sex, 2 to 5 days old, were obtained from local farms. Usually 2 piglets were from the same litter. The piglets were anaesthetised with halothene; their hearts rapidly removed and washed free of blood with warm solution containing (mM):120 Na +, 5 K+, 2.25 Ca2+,
0.5 Mg2+, 98.5 Cl", 0.5 SO^", 34 HC03 ", 1 HP04 2",
0.04 EDTA, deionised and double distilled water in glass, equilibrated with 95% 02 and 5% C02.
After dissection of the right atrium in warm solution, the tissue was set up in an apparatus with a 50 ml. bath (Blinks, 1965 J. Appl. Physiol. 20, 755-757), containing the solution described above supplemented with (mM) :15 Na+, 5 fumarate, 5 pyruvate, 5 L-glutamate, 10 glucose. Experiments were carried out at 37°C. For the study of positive chronotropic effects, the spontaneously beating right atrium was suspended at a resting tension just sufficient for measurable development of tension (to avoid tachycardia induced by stretching the sinoatrial node - Blinks, 1956 Amer. J. Physiol. 186, 299-303) . The tissue was attached to a Swema SG4-45 strain gauge transducer by means of a stainless steel wire and force recorded on a Watanabe polygraph.
To avoid possible indirect β-adrenoceptor-mediated effects due to release of noradrenaline all experiments were carried out in the presence of 400 nM (+)-propranolol (about 100 x KB for (+)-propranolol) . To reduce tissue capture of 5-HT, all experiments were carried out in the presence of 6 μM cocaine; cocaine potentiates the effects of 5-HT on human atrium [Kaumann et al., Br. J. Pharmacol. 100, 879-885, (1990)]. To decrease oxidation of 5-HT the physiological solution and all dilutions of 5-HT contained 0.2 mM ascorbate.
A single cumulative concentration-effect curve was determined by the sequential addition of 5-HT or other agonists to the bath in amounts that increased the total concentration in steps of log unit. Enough time was allowed for each effect to reach equilibrium. The experiments were terminated by the administration of a saturating concentration of (-)-isoprenaline (0.2 mM) . The time of incubation with an antagonist was at least 1 hr before a concentration-effect curve for an agonist was determined.
Results
In the above screen, the potency of a number of known agonists was found to be similar to that published for human atrium [Kaumann et al., Br. J. Pharmacol. 100, 879-885, (1990)]. These results are consistent with the hypothesis that the 5-HT receptors of porcine sinoatrial node and of human right atrial appendage are the same.
The preliminary screening results shown in Table 1 indicate that (3-α-tropanyl)-lH-indazole-3-carboxylic acid ester is a competitive antagonist of cardiac 5-HT4 receptors.
TABLE 1
Comparison of blocking potencies of antagonists on right atrial preparations
Porcine (rate) Human (force)
pK n pK n
(3-α-tropanyl)- lH-indazole-3- carboxylic acid ester 7.1 6 ND
Granisetron ineffective 3 ineffective (EP-200444-A) (1 μM) (20 μM)
pK -log M equilibrium dissociation constant ND not determined n number of individuals

Claims

Claims .
1. A cardiac 5-HT4 receptor antagonist for use in the treatment of atrial arrhythmias.
2. A cardiac 5-HT4 receptor antagonist or use in reducing the occurrence of stroke.
3. The use according to claim 1 or 2 in which the 5-HT4 receptor antagonist is (3-α-tropanyl)-1H- indazole-3-carboxylic acid ester.
EP91908623A 1990-04-26 1991-04-24 Use of 5-ht4-receptor antagonists in the treatment of atrial fibrillation, including the prevention of stroke Expired - Lifetime EP0526540B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9009389 1990-04-26
GB909009389A GB9009389D0 (en) 1990-04-26 1990-04-26 Treatment
PCT/GB1991/000650 WO1991016045A2 (en) 1990-04-26 1991-04-24 Use of 5-ht4 receptor antagonists in the treatment of arrythmias and stroke

Publications (2)

Publication Number Publication Date
EP0526540A1 true EP0526540A1 (en) 1993-02-10
EP0526540B1 EP0526540B1 (en) 1999-06-30

Family

ID=10675031

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91908623A Expired - Lifetime EP0526540B1 (en) 1990-04-26 1991-04-24 Use of 5-ht4-receptor antagonists in the treatment of atrial fibrillation, including the prevention of stroke

Country Status (14)

Country Link
EP (1) EP0526540B1 (en)
JP (2) JPH05509293A (en)
AT (1) ATE181668T1 (en)
AU (1) AU653521B2 (en)
CA (1) CA2081344C (en)
DE (1) DE69131398T2 (en)
DK (1) DK0526540T3 (en)
ES (1) ES2134774T3 (en)
GB (1) GB9009389D0 (en)
GR (1) GR3031042T3 (en)
IE (1) IE911383A1 (en)
PT (1) PT97477B (en)
WO (1) WO1991016045A2 (en)
ZA (1) ZA913071B (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020128172A1 (en) 1991-12-21 2002-09-12 Smithkline Beecham Plc Use of 5-HT4 modulators for the manufacture of a medicament for the treatment of the bladder diseases
US5852014A (en) * 1992-03-12 1998-12-22 Smithkline Beecham P.L.C. Condensed indole derivatives as 5HT4 -receptor antagonists
US5998409A (en) * 1992-03-12 1999-12-07 Smithkline Beecham Plc Condensed indole derivatives as 5HT4 -receptor antagonists
JPH08502283A (en) * 1992-10-16 1996-03-12 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 5-HT 4) Fused ring system N-alkylpiperidinyl-4-methylcarboxylic acid ester / amide for receptor antagonist
GB9301660D0 (en) * 1993-01-28 1993-03-17 Smithkline Beecham Plc Pharmaceuticals
CA2160420A1 (en) * 1994-10-20 1996-04-21 Haruhiko Kikuchi 5-ht4 receptor agonists
EP1311295A2 (en) * 2000-08-07 2003-05-21 Laboratoire Glaxosmithkline S.A.S. Use of 5ht4 receptor antagonists in the manufacture of a medicament for the prophylaxis or treatment of atrial fibrillation
GB0211230D0 (en) 2002-05-16 2002-06-26 Medinnova Sf Treatment of heart failure
AU2005254800B2 (en) 2004-06-15 2010-12-09 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
EP2153830A1 (en) * 2008-08-07 2010-02-17 Sanofi-Aventis Use of dronedarone for the preparation of a medicament intended for the prevention of stroke or transient ischemic attack
EP3176164B1 (en) 2014-07-30 2019-08-21 Aetas Pharma Co. Ltd. Optical isomer of 1,4-benzothiazepine-1-oxide derivative, and pharmaceutical composition prepared using same

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3687080T2 (en) * 1985-04-27 1993-03-25 Beecham Group Plc AZABICYCLONONYL INDAZOL CARBOXAMIDE WITH 5-HT ANTAGONISTIC EFFECT.
US4731643A (en) * 1985-10-21 1988-03-15 International Business Machines Corporation Logic-circuit layout for large-scale integrated circuits

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9116045A3 *

Also Published As

Publication number Publication date
DE69131398D1 (en) 1999-08-05
ZA913071B (en) 1992-11-25
GB9009389D0 (en) 1990-06-20
JP2003267890A (en) 2003-09-25
CA2081344A1 (en) 1991-10-27
EP0526540B1 (en) 1999-06-30
IE911383A1 (en) 1991-11-06
DE69131398T2 (en) 2000-03-02
ATE181668T1 (en) 1999-07-15
WO1991016045A2 (en) 1991-10-31
AU653521B2 (en) 1994-10-06
PT97477A (en) 1992-01-31
CA2081344C (en) 2003-10-21
GR3031042T3 (en) 1999-12-31
ES2134774T3 (en) 1999-10-16
DK0526540T3 (en) 1999-11-22
PT97477B (en) 1998-08-31
JPH05509293A (en) 1993-12-22
WO1991016045A3 (en) 1991-12-26
AU7768091A (en) 1991-11-11

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